We are among those who have done pioneering work in demonstrating that endothelin-1 (ET) is a novel transmitter or modulator in the CNS. We have found that cerebellar granule cells not only synthesize and release ET upon stimulation, but also express ET-specific receptors coupled to phospholipase C. Stimulation of ET receptors leads to release of preloaded D-aspartate, a marker for endogenous glutamate, from these neurons. Both receptor-mediated activation are strictly dependent on extracellular calcium; however, this calcium dependence does not involve voltage- sensitive calcium channels or Na+/Ca 2+ exchange. Detailed biochemical and pharmacological characterization reveal that ET-induced transmitter release may involve phosphoinositide metabolism as well as other receptor-mediated events. Indeed, we have recently provided evidence that ET stimulates a marked increase in free intracellular calcium, i.e., [Ca 2+]i, and this effect is mainly due to Ca 2+ influx through ET receptor-operation cation channels. This Ca 2+ entry is positively regulated by protein kinase C and blocked by inorganic Ca 2+ antagonists such as La 3+, Mn 2+ and Cd 2+. This ET receptor-gated Ca 2+ influx has a prominent role in the sustained increase of phosphoinositide breakdown and may be intimately coupled to the mitogenic activity of this neuropeptide on glial cells. Preliminary results of Dr. Fukamauchi and co-workers show that ET induces a rapid increase of c-fos and m3 receptor-mRNA in cerebellar granule cells, supporting a major role of ET in neuronal gene expression.